The present invention relates to compounds of the formula ##STR2## wherein R.sub.1 is selected from the group consisting of hydrogen, amino, halogen and nitro; R.sub.2 is selected from the group consisting of hydrogen, lower alkyl, carboxylic acids, esters and primary, secondary or tertiary amides thereof, alkylhydroxy, acylhydroxy-lower alkyl, amino-lower alkyl, alkylamino-lower alkyl, acylamino-lower alkyl and carboxaldehyde; and X is hydrogen or halogen and the pharmaceutically acceptable salts thereof.
As used in this disclosure, the term "lower alkyl" or "alkyl" comprehends both straight, cyclo and branched chain (C.sub.1 -C.sub.7) carbon-hydrogen radicals, preferably C.sub.1 -C.sub.4 carbon-hydrogen radicals such as methyl, ethyl, propyl, isopropyl, butyl and the like.
The term "halogen" is used to include all four forms thereof, i.e., chlorine, bromine, fluorine and iodine.
By the term "acyl" is meant a C.sub.1 to C.sub.7, preferably a C.sub.1 to C.sub.4, alkanoic acid moiety, i.e., radicals of the formula ##STR3## wherein R is C.sub.1 -C.sub.6 or hydrogen, e.g., acetyl, propionyl, butyryl and the like.
By the term "carboxylic acids and esters thereof" is meant moieties of the formula ##STR4## wherein R is hydrogen or lower alkyl.
By the term "primary, secondary or tertiary amides of carboxylic acids" is meant moieties of the formula ##STR5## wherein R is either hydrogen or lower alkyl and may be the same or different.
By the term "acylhydroxy lower alkyl" is meant a moiety of the formula ##STR6## wherein R is lower alkyl.
By the terms "amino-lower alkyl", "acylamino-lower alkyl" and alkylamino-lower alkyl" are meant a moiety of the formula ##STR7## wherein R.sub.3 and R.sub.4 are hydrogen or R.sub.3 is hydrogen and R.sub.4 is acyl as defined above or lower alkyl or R.sub.3 and R.sub.4 are both alkyl.
The following reaction scheme sets forth the methods of preparation utilized to produce the novel compounds of the present invention. ##STR8## wherein X is hydrogen or halogen and R is selected from the group consisting of CO.sub.2 R.sub.5 and CH.sub.2 OR.sub.6 wherein R.sub.5 is lower alkyl and R.sub.6 is acetyl.
The above reaction is carried out in the presence of an alkali metal hydride such as sodium or potassium hydride in a non-aqueous polar solvent such as dimethylformamide or dimethylsulfoxide. The reaction temperature may vary in the range of about 0.degree. C. to 100.degree. C. with a preferred range of 0.degree. C. to 65.degree. C. ##STR9## wherein X is as above and R is the group CO.sub.2 R.sub.5 wherein R.sub.5 is lower alkyl.
The above reduction of the nitro group to an amino group may be carried out by any suitable agent but a preferred reducing agent would be stannous chloride dihydrate. Where one desires, any reducing agent that will selectively reduce a nitro group may be utilized. The solvent can be an aqueous acid, e.g., HCl, and the reaction carried out at a temperature range of 0.degree. C.-100.degree. C. with room temperature preferred. ##STR10## wherein R and X are as in Step 2 and R.sub.1 is hydrogen or halogen.
The above reaction represents the well known "Sandmeyer reaction" wherein an amino group is replaced by different substituents, e.g., halogen (chloro, fluoro, bromo or iodo). The reactants utilized in the above "Sandmeyer reaction" are a mixture of sodium nitrite and cuprous chloride in hydrochloric acid which is utilized as a solvent to give the chloro substituent in this case. The other substituents may be arrived at by utilizing analogous reactants such as cuprous bromide, potassium iodide or fluoroboric acid. If desired, the amino group can also be replaced by hydrogen by means of reacting the diazonium salt with hypophosphorous acid. ##STR11## wherein R, R.sub.1 and X are as in Step 3.
The above reaction represents the conversion of the benzophenone moiety to its oxime utilizing, e.g., hydroxylamine hydrochloride in a suitable inert solvent such as ethanol, or pyridine at reflux temperatures to room temperature, preferably at reflux. Utilization of such a process step is found in U.S. Pat. No. 2,893,992 cited for reference. ##STR12## wherein R, R.sub.1 and X are as in Step 3.
The above reaction represents a modified Clemmensen reduction to produce the desired lactam. To achieve the above end product a combination of zinc in acetic acid together with a catalytic amount of a mineral acid, e.g., hydrochloric acid, is utilized at about 25.degree. C. to 100.degree. C. with about 70.degree. C. preferred. ##STR13## wherein R, R.sub.1 and X are as in Step 3.
The above reaction represents a specific reduction step of the cyclic amide function. The reduction is carried out utilizing a borohydride reducing agent, e.g., diborane, at reflux temperature in an inert solvent such as tetrahydrofuran or long chain ethers, e.g., glyme and diglyme with THF preferred. ##STR14## wherein R, R.sub.1 and X are as in Step 5.
If desired, reduction of both the ester and amide functions can be carried out in one step utilizing a borohydride reducing agent, e.g., borane methyl sulfide, in an inert solvent such as the ethers alluded to in Step 6 at reflux temperatures to room temperatures with reflux preferred. ##STR15## wherein X and R.sub.1 are as in Step 5.
The above oxidation step of the amino alcohol to the aldehyde and of the amine to the imine is carried out utilizing manganese dioxide in the presence of an inert solvent such as tetrahydrofuran or methylene chloride at room temperature to reflux temperature with room temperature preferred. ##STR16## wherein R.sub.1 and X are as in Step 5.
In the above reaction step the dihydrobenzodiazepine (IX) is oxidized with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) in any inert solvent such as benzene or toluene at about reflux temperature to yield the desired benzodiazepine (XII) and minor amounts of the isomeric 6H benzodiazepine (XI) which may be removed by chromatography or recrystallization. ##STR17## wherein X and R.sub.1 are as in Step 5.
The above reaction step consists of the oxidation of the compound of formula XII with manganese dioxide utilizing the solvents and temperature ranges set forth in Step 8. ##STR18## wherein X and R.sub.1 are as in Step 5.
In the above reaction step the aldehyde (X) is reacted with an alcohol, e.g., a methanolic or ethanolic solution of sodium cyanide and the resulting acylcyanide oxidized in situ with manganese dioxide to the desired ester (XIII). ##STR19## wherein R.sub.1 and X are as in Step 5.
The ester function in compounds of the formula XIII may then be hydrolyzed by refluxing in a dilute mineral acid, e.g., dilute hydrochloric acid, to produce the corresponding carboxylic acid derivative (XIV). ##STR20## wherein R.sub.1 and X are as in Step 5.
Compounds of the formula XIII may thereafter be converted to primary, secondary or tertiary amides (XVII, XVI and XV, respectively) by reaction with primary, secondary or tertiary amines in the presence of a lower alkanol, e.g., ammonia, monomethylamine, diethylamine, etc., in methanol, ethanol, etc., at from room temperature to reflux temperature, preferably at the reflux temperature of the solvent. ##STR21## wherein R, R.sub.1 and X are as in Step 5.
Compounds of the formula VI are reacted with a borohydride reducing agent e.g., sodium borohydride, in an inert solvent such as an alkanol, e.g., ethanol or an ether, e.g., tetrahydrofuran, to produce the reduced alcohol. The reaction is carried out at room temperature to reflux temperature with reflux temperature preferred. ##STR22## wherein R.sub.1 and X are as in Step 5.
Compounds of the formula XVIII are thereafter oxidized with manganese dioxide utilizing the solvents and temperature ranges of Step 8, to the aldehyde (XIX). ##STR23## wherein R.sub.1 and X are as in Step 5.
Compounds of the formula XIX thereafter undergo a Wolff-Kishner reduction, i.e., treatment of the aldehyde (XIX) with hydrazine hydrate or free hydrazine in a lower alkanol, e.g., methanol, ethanol, etc., followed by treatment with an alkali metal hydroxide such as potassium t-butoxide utilizing an inert solvent such as toluene, benzene, xylene, etc. ##STR24## wherein R.sub.1 and X are as in Step 5.
The compound of the formula XX is initially reacted with a borohydride reducing agent, e.g., borane methyl sulfide, at temperature ranges and utilizing solvents as set forth in Step 7. After reduction of the amide compound is complete, the reaction mixture is thereafter oxidized utilizing 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) as the oxidizing agent utilizing solvents and temperature ranges as disclosed in Step 9 above.
The end products such as compounds X, XII, XIII, XIV, XV, XVI, XVII, XX wherein R.sub.1 is amino can, if desired, be converted to the end products wherein R.sub.1 is nitro by means of a Sandmeyer reaction. Other methods for the preparation of pyrazolobenzodiazepines wherein R.sub.1 is nitro are set forth below. ##STR25## wherein X is as in Step 5.
The above reaction step consists of the nucleophilic displacement reaction of the fluorobenzophenone with the pyrazolodiacetate utilizing the reactants, solvents and temperature ranges as set forth in Step 1 above. ##STR26## wherein X is as in Step 5.
The crude diacetate (XXII) is hydrolyzed directly with an aqueous mineral acid such as HCl to give the dialcohol compound (XXIII). The reaction is preferably carried out at reflux temperature but a range of room temperature to reflux temperature can be utilized. ##STR27## wherein X is as in Step 5.
The dialcohol compound (XXIII) is converted to the dichloro compound (XXIV) by reaction of compound XXIII with thionyl chloride at 40.degree. C. to reflux temperature with reflux preferred. ##STR28## wherein X is as in Step 5.
Thereafter the dichloro compound undergoes a nucleophilic displacement by reaction with an alkali metal phthalimide, e.g., potassium, in an inert solvent such as dimethylformamide or dimethylsulfoxide at a temperature of 0.degree. C. to 100.degree. C., preferably at 65.degree. C., to provide the diphthalimido product (XXV). ##STR29## wherein X is as in Step 5.
The compound of the formula XXV is thereafter reacted in an alcoholic solution, e.g., methanol or ethanol, with an excess of hydrazine, e.g., hydrazine hydrate, at reflux temperatures to provide the cyclized amino compound (XXVI). ##STR30## wherein X is as in Step 5.
The above reaction is accomplished by treatment of the amino compound (XXVI) with an acetylating agent, e.g., acetic anhydride, in situ in an inert solvent to provide the amide (XXVII). If desired, XXVII can be alkylated with an alkyl halide after first forming the alkali metal salt of the amide. Examples of such alkylation are well known in the art. Further, the acyl group can be hydrolyzed to yield the alkylaminoalkyl group which can be alkylated to the dialkylaminoalkyl group. ##STR31## wherein X is as in Step 5.
The above reaction is carried out by diazotization of the amide (XXVI) in a solvent such as an aqueous acid, e.g., a mixture of acetic acid and water. The diazotization reaction is carried out utilizing sodium nitrite in water at a temperature range of 0.degree. C. to 20.degree. C., preferably at 10.degree. C. ##STR32## wherein X is as in Step 5.
The alcohol (XXVII) is thereafter oxidized to the aldehyde (XXVIII) following conditions set forth in Step 15 above. ##STR33## wherein X is as in Step 5.
The aldehyde (XXVIII) undergoes a Wolff-Kishner reduction as set forth in Step 16 above.
The compounds of the present invention exhibit pharmacological activity as anxiolytics, sedatives, muscle relaxants and anticonvulsants. As contemplated by this invention, the novel compounds of the present invention and their pharmaceutically acceptable salts can be embodied in pharmaceutical dosage formulations containing from about 0.1 to about 40 mg., most preferably 1-40 mg., with the dosage adjusted to species and individual patient requirements. The novel compounds and their pharmaceutically acceptable salts can be administered internally, for example, parenterally or enterally, in conventional pharmaceutical dosage forms. For example, they can be incorporated in conventional liquid or solid vehicles such as water, gelatin, starch, magnesium stearate, talc, vegetable oils and the like to provide talbets, elixirs, capsules, solutions, emulsions and the like according to acceptable pharmaceutical practices.
Preferred species of the compounds of the present invention are those of the formula ##STR34## wherein R.sub.7 is CONHCH.sub.3, CONH.sub.2 or CON(CH.sub.3).sub.2 and the formula ##STR35## wherein R.sub.8 is CH.sub.2 OH, CH.sub.2 NH.sub.2 and CH.sub.2 NHCOCH.sub.3.
The expression "pharmaceutically acceptable salts" is used to include both inorganic and organic pharmaceutically acceptable acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, citric acid, formic acid, maleic acid, acetic acid, succinic acid, tartaric acid, methanesulfonic acid, paratoluenesulfonic acid and the like. Such salts can be formed quite readily by those skilled in the art, with the prior art and the nature of the compound to be placed in salt form, in view.